Inhibition of prolyl hydroxylase domain proteins selectively enhances venous thrombus neovascularisation.
Thromb Res
; 169: 105-112, 2018 09.
Article
de En
| MEDLINE
| ID: mdl-30031289
ABSTRACT
BACKGROUND:
Hypoxia within acute venous thrombi is thought to drive resolution through stabilisation of hypoxia inducible factor 1 alpha (HIF1α). Prolyl hydroxylase domain (PHD) isoforms are critical regulators of HIF1α stability. Non-selective inhibition of PHD isoforms with l-mimosine has been shown to increase HIF1α stabilisation and promote thrombus resolution.OBJECTIVE:
The aim of this study was to investigate the therapeutic potential of PHD inhibition in venous thrombus resolution.METHODS:
Thrombosis was induced in the inferior vena cava of mice using a combination of flow restriction and endothelial activation. Gene and protein expression of PHD isoforms in the resolving thrombus was measured by RT-PCR and immunohistochemistry. Thrombus resolution was quantified in mice treated with pan PHD inhibitors AKB-4924 and JNJ-42041935 or inducible all-cell Phd2 knockouts by micro-computed tomography, 3D high frequency ultrasound or endpoint histology.RESULTS:
Resolving venous thrombi demonstrated significant temporal gene expression profiles for PHD2 and PHD3 (Pâ¯<â¯0.05), but not for PHD1. PHD isoform protein expression was localised to early and late inflammatory cell infiltrates. Treatment with selective pan PHD inhibitors, AKB-4924 and JNJ-42041935, enhanced thrombus neovascularisation (Pâ¯<â¯0.05), but had no significant effect on overall thrombus resolution. Thrombus resolution or its markers, macrophage accumulation and neovascularisation, did not differ significantly in inducible all-cell homozygous Phd2 knockouts compared with littermate controls (Pâ¯>â¯0.05).CONCLUSIONS:
This data suggests that PHD-mediated thrombus neovascularisation has a limited role in the resolution of venous thrombi. Directly targeting angiogenesis alone may not be a viable therapeutic strategy to enhance venous thrombus resolution.Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Pipérazines
/
Pyrazoles
/
Pyridones
/
Thrombose
/
Benzimidazoles
/
Procollagen-Proline Dioxygenase
/
Néovascularisation physiologique
/
Hypoxia-inducible factor-proline dioxygenases
Type d'étude:
Prognostic_studies
Limites:
Animals
/
Female
/
Humans
/
Male
Langue:
En
Journal:
Thromb Res
Année:
2018
Type de document:
Article
Pays d'affiliation:
Royaume-Uni